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Which Cancers are ‘Rare’? Depends on Where You Are

For example, a rare cancer in the United States is considered to be a malignancy that affects fewer than 200,000 people, but in Europe it is defined as a cancer with a prevalence affecting fewer than five out of 10,000 people, meaning that what is rare on one continent may be considered common across the pond.

And then there is the whole issue of using prevalence rather than incidence, since prevalence can possibly distort the figures when an uncommon cancer with a longtime survival provides larger numbers than a more common cancer that claims more lives sooner, notes Paolo Casali, MD, a medical oncologist at Instituto Nazionale dei Tumori in Milan and a member of the European Society for Medical Oncology's executive committee, who is spearheading the society's European Action Against Rare Cancer (EAARC) www.rarecancers.eu) call to action.

According to ESMO, some 2.5 million Europeans are affected by rare cancers and each year 400,000 people in Europe are newly diagnosed with rare cancers and 240,000 die from them.

As the society says, the ESMO initiative plans to place rare cancers on the European policy agenda since rare cancers cumulatively represent more than 20% of all cancers in Europe and are therefore more common than people think.

The call to action deals with more than merely developing effective treatments; there are economic, social, and political implications involving the unique structure of the European Union and its relationship with its various member nations.

And, according to Robert Schaefer, EAARC senior project manager, the rare cancer experience in Europe may have potential ramifications for the future of oncology: “We're not just looking at what is defined as rare cancers in Europe, but also looking toward the future of oncology, with molecular oncology identifying rare types of cancer within so-called common cancers,” he said during a telephone interview from Berlin.

(Disclosure note—I had worked with Mr. Schaefer several years ago when we were both involved with Vital Options International and the Group Room radio show.)

“The definition of rare cancers in Europe also has regulatory implications, since if a therapy is granted orphan drug status it means the company filing for market approval can use a less costly procedure and gain incentives like market exclusivity when the drug is approved.”

Prevalence vs Incidence

Dr. Casali, who spoke to OT from Milan via telephone, chaired a news briefing last month at ESMO's 35th annual Congress that included patients, caregivers, oncologists, pharmaceutical companies, researchers, and policymakers who discussed the battle against rare cancers in Europe to improve outcomes.

He said that he thought incidence was a better indicator for determining rare cancers, but the European definition, as well as the one used in the United States, was based on prevalence, which is also applied to all rare diseases.

“There is a problem when rare cancers are based on prevalence—the number of patients with the same diagnosis in the population at a given time—while incidence is the number of newly diagnosed cancers in a year. We proposed a definition based on incidence—meaning five or six new cases per 100,000 each year.”

He said prevalence is affected by mortality, so if a disease is associated with a long life expectancy you will have more patients at a given time because you've got those diagnosed this year and all those diagnosed in past years.

“Prevalence is an indication very much affected by life expectancy, while incidence is not. Prevalence is used as the definition for rare diseases because most rare diseases are chronic, and, for example, diabetics need insulin every day so the prevalence of diabetic patients is useful to understand how much insulin you will need for the population. It is a good definition for rare diseases but not a good definition in our view for rare cancers.

“Rare cancers are different, because if you have a rare tumor associated with a long life expectancy, such as testicular cancer, which is very frequently cured, the prevalence will be quite high, while with a frequent cancer such as small-cell lung cancer, which is high in incidence but has a low life expectancy, the prevalence will be low. So paradoxically, you may be led to believe that some frequent cancers are rare and some rare cancers are frequent.

“The other problem is,” he continued, “that if you define rare cancers as rare diseases and use prevalence as the indicator, then practically speaking probably something like 50 percent of cancers are rare, which is quite untenable, because you cannot hold the view that 50 percent of cancer cases are rare.

“In theory, the problem is not how many cancers overall are rare, but how many patients do you have with a single rare cancer? Even with a conservative definition like ours, you still end up with many cancer cases being rare.”

Dr. Casali said he considered as rare, among others, cancers of the thorax such as mesothelioma, testicular cancer, endocrine tumors, sarcomas, many if not all cancers of the central nervous system, some skins cancers, some digestive cancers such as tumors of the anal canal or gall bladder, many head and neck cancers, all the pediatric cancers, and some hematological cancers.

39 Political Recommendations

Mr. Schaefer said the goal of EAARC is to implement the 39 political recommendations made at a 2008 consensus conference, “Rare Tumors in Europe: Challenges and Solutions,” held in Brussels, adding “there is one word we take very seriously—action.”

The 39 recommendations fall into three umbrella categories:

Improving the methodology of clinical studies in rare cancers by organizing symposia that would look at smaller, shorter trials to help bring therapies to market sooner, and that would present position papers in “meaningful and understandable language” to policy decision makers throughout Europe.

* Improving the organization of health care of rare cancers by creating collaborative networks through advocacy initiatives that would provide a clearinghouse for information about centers of excellence in rare diseases in Europe.

* Improving both access to new therapies in Europe for rare cancer patients, and access to clinical expertise across Europe, including assessing how individual national cancer plans reflect both rare cancers and other rare diseases.

The third point is noteworthy because some therapies approved as safe and effective by the European Medicines Agency that have also received marketing approval by the European Commission are not made available to many patients based on cost effectiveness, especially in some areas of Eastern Europe, and these patients will not be reimbursed by their respective governments even if they seek care in other European nations.

Other factors that affect rare cancers include late diagnoses and misdiagnoses, and the fact that many European governments and cancer control organizations have made prevention, screening, and healthy lifestyle campaigns a priority in their anti-cancer efforts, which have little bearing on certain rare cancers, such as brain tumors.

United States: Only Lung Cancer Not Rare?

In the United States, the 200,000 person threshold means that only lung cancer (with 219,440 new cases) would qualify as not being rare, since according to the most recent American Cancer Society statistics, no other cancer exceeded 200,000 cases. For example, breast cancer had about 194,000 cases and prostate cancer about 192,000.

Gary D. Hammer, MD, PhD, the Millie Schembechler Professor of Adrenal Cancer, Director of the Endocrine Oncology Program, and Director of the Center for Organogenesis at the University of Michigan, noted that the 200,000 figure was legislated through the Rare Diseases Act of 2002.

He said that using the Act's definition would make almost all cancers rare, since more than 95% of all cancers affect fewer than 200,000 people, and noted that researchers at an NCI Epidemiology Leadership Workshop in 2005 recommended that rare cancers be defined as 40,000 or fewer cases per year, but the recommendation never gained traction.

Focusing on the 40,000-patient threshold, though, would still mean that 80% of cancers would be considered rare, he said.

“The goal for us involved in rare cancer legislation has not been to encumber as many people and conditions as we can, but to take care of the truly disenfranchised, and the truly disenfranchised are not every cancer patient—which for some cancers like breast and colon have big lobbying groups and funding mechanisms—but to take care of the cancer types for which there is only one doctor or no doctors in the United States who know what that cancer is and how to deal with it.”

‘Ultra-Rare’

Dr. Hammer said he had served as a consultant on rare cancers to the Kennedy-Hutchinson 21st Century Cancer ALERT (Access to Lifesaving Early Detection, Research, and Treatment) Act introduced in the Senate in 2009, but that the version that reached the Senate no longer contained language dealing with rare cancers.

“We are stuck with the challenge of the legislation that uses this definition of rare cancer, so ‘ultra-rare’ cancer was chosen as a different word to allow discourse about rare cancers, being something different from the definition of a rare disease,” he said.

An ultra-rare cancer must meet one or more of these criteria:

* Incidence of fewer than one in 100,000 people per year, which in 2009 would be the equivalent of fewer than 3,000 new cases a year.

* An inherited cancer or any inherited syndrome that includes the occurrence of one or more types of cancer.

* Variants of common cancers characterized by genetic or cytogenetic abnormalities.

* Variants of common cancers characterized by specific biological behavior different from that cancer type's typical biological behavior.

* Variants of common cancers confined to a specific demographic or ethnic group, or clinical settings, or specific etiology (except for those caused by smoking).

As for other rare-cancer initiatives in the United States, the American Society of Clinical Oncology is planning to convene a panel of experts to address issues related to clinical trials in small or rare populations in December, which will be followed by a joint NCI-ASCO conference on “Overcoming Barriers to International Clinical Trials for Rare Cancers,” where results from the consensus panel trial design in small populations will be reported.

European Action Against Rare Cancer Partners

In addition to ESMO, EAARC's other partners include the European Organization for Rare Diseases (Eurordis), the European Cancer Patient Coalition (ECPC), CONTICANET, the Association of European Cancer Leagues (ECL), the Chronic Myeloid Leukemia Support Group, the International Brain Tumor Alliance (IBTA), Orphanet, the Chronic Myeloid Leukemia Advocates Network, the European Institute of Oncology (IEO), and the Fondazione IRCCS Istituto Nazionale dei Tumori, as well as Novartis Oncology as the founding sponsor. Other corporate sponsors are Amgen, Bristol-Myers Squibb, Pfizer Oncology, Novartis Oncology, MSD Oncology, Celgene, Alexion Europe, EuropaBio, and PharmaMar.

EAARC states that all organizational members collaborate as equal partners, with decisions based on consensus.

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